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WO1999065881A1 - Composes heterocycliques utilises comme agents hypoglecymiques - Google Patents

Composes heterocycliques utilises comme agents hypoglecymiques Download PDF

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Publication number
WO1999065881A1
WO1999065881A1 PCT/JP1999/003214 JP9903214W WO9965881A1 WO 1999065881 A1 WO1999065881 A1 WO 1999065881A1 JP 9903214 W JP9903214 W JP 9903214W WO 9965881 A1 WO9965881 A1 WO 9965881A1
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group
meo
compound
pro
hydrogen atom
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PCT/JP1999/003214
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English (en)
Inventor
Mikio Suzuki
Keisuke Ohdoi
Katsuhiro Kato
Hiromitsu Matsumoto
Koji Toyama
Masaki Kitahara
Takashi Yotsumoto
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Nissan Chemical Industries, Ltd.
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Priority to AU41670/99A priority Critical patent/AU4167099A/en
Publication of WO1999065881A1 publication Critical patent/WO1999065881A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel 6-membered heterocyclic-compounds having a hypoglycemic effect, which are useful in medical and veterinary fields, particularly useful for preventing and treating diabetes and diabetic complications.
  • various sulfonylureas and biguanides have been widely used as oral hypoglycemic agents for lowering blood glucose level.
  • these agents have probabilities of causing serious hypoglycemic coma and lactic acidosis, and therefore every possible care must be taken for practical use.
  • Recently developed insulin sensitizers also have a hypoglycemic effect, they are particularly useful for obese Type II diabetes, and are noted as agents which hardly cause such hypoglycemic symptoms as caused by the above-mentioned oral hypoglycemic agents.
  • an adequate effect can not be obtained for patients with deficiency of insulin secretion.
  • the above-mentioned agents do not necessarily lower the blood glucose level during starvation.
  • CPT carnitine-palmitoyl transferase
  • Said CPT inhibitors have an effect of effectively lowering the blood glucose level.
  • their usefulness for preventing onset and progression of various complications caused by diabetes such as diabetic nephropathy, diabetic retinopathy, diabetic cataract, diabetic neuropathy and the like, has not been completely proved.
  • a CPT inhibitor suppresses the im uno pathological changes in kidney caused in db/db mice as models of Type II diabetes (Diabetes, vol.31, 12-18, 1982). Further, the progression of such complications is suppressed by strict control of blood glucose level. Accordingly, the CPT inhibitors are useful as pharmaceutical agents for preventing and treating such complications.
  • the CPT inhibitors have a strong effect for lowering ketone body level in the diabetic animals and diabetic patients (Proc. Soc. Exp. Biol. Med., vol.178, 288-296, 1985, Metabolism, vol.40, 1185-1190, 1991). It is expected that the CPT inhibitors inhibit all pathological conditions caused by cellular pathologically accelerated formation of ketone bodies as well as diabetes.
  • the present inventors have synthesized various 6-membered heterocyclic- compounds which are not disclosed in the above-mentioned literatures, and have studied the their properties. As the result, the present inventors have found a compound having more excellent hypoglycemic effect.
  • the present invention provides 6-membered heterocyclic- compounds capable of preventing and treating diabetes mellitus and diabetic complications.
  • the present invention relates to a 6- membered heterocyclic-compound or its salt represented by the formula [i] :
  • R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P0 2 H 2 , ⁇ 6
  • C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom
  • R which are independent of each other, is a hydrogen
  • R is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an amidino
  • 11' ' R which are independent of one another, is a C 1 _ 7 alkyl
  • each of R and R which are independent of each other, is a C ⁇ _ 7 alkyl group, R is a hydrogen atom, a C ⁇ 7 alkyl group, a C ⁇ _ 7 aliphatic acyl group, a C 5 _ :3 aromatic acyl group or a protecting group ⁇ ;
  • D is a covalent bond, -CH,-, -0-, -S-, -S(0)-, -S(0) 2 -, -NR 12 -, -C(0)-NR 12 -, -NR 12 -C(0)- or -NR ⁇ '-C (0) -NR 12 - (each of R 12 and R 12' which are independent of each other, is a hydrogen atom or a C ⁇ , alkyl group) ;
  • each of R , R , R ' and R which are independent of one another, is a hydrogen atom, a halogen atom, a hydroxyl group, a C 1 _ 7 alkyl group or a C 1 _ 7 alkoxy group, each of
  • R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a sulfonic acid group, a sulfonamide group, P0 2 H 2 , P0 3 H 2 , a 5-tetrazolyl
  • C(0)NRR (each of R and R which are independent of each other, is a hydrogen atom or a C ⁇ _ 7
  • R is a hydrogen atom or a C._ 7 alkyl group
  • R is more preferably C(0)0R °
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • R may be a hydrogen atom, a halogen atom, a nitro group, a cyano group, a formyl group, a guanidyl group, an ami .dm. o group, NR ⁇ oR 10 ' (,eac,h or R 10 and R 10 ' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group, C 1 _ 7 aliphatic acyl, C 6 _ 10 aromatic acyl or a
  • R R R (each of R , R and R which are independent of one another, is a C._ 7 alkyl group) ; it is preferably a guanidyl group, an amidino group,
  • R R R (each of R , R and R which are independent of one another, is a C 1 _ 7 alkyl group) , it is
  • R R R (each of R , R and R which are independent of one another, is a C 1 7 alkyl group) ;
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, it is preferably a fluorine atom, a chlorine atom or a bromine atom;
  • each of R and R " which are independent of each other, may be a C 1-7 alkyl group;
  • the C 1 _ 1 alkyl group may be methyl, ethyl, n-prop
  • R may be a hydrogen atom, a C 1 _ 7 alkyl group, C,_ 7 aliphatic acyl, C 6 _ 1 classroom aromatic acyl or a protecting group, it is preferably a hydrogen atom or a C 1-7 alkyl group;
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like;
  • the C 1 _ 7 aliphatic acyl may be formyl, acetyl, propionyl, butyryl , isobutyryl, valeryl, isovaleryl, pivaloyl or the like;
  • the C 6 _ 10 aromatic acyl may be benzoyl, 2-toluoyl, 3- toluo
  • aryloxymethyl group such as 30M: benzyloxymethy1 , PMBM: p-methoxybenzyloxymethyl or p-AOM: P-anisyloxymethyl, preferably e.g.
  • benzyloxymethyl , a C ⁇ _ 4 alkylaminomethyl group (such as dimethylaminomethyl) a substituted acetamidomethyl group (such as Acm: acetamidomethyl or Tac : trimethylacetamidomethyl) , a substituted thiomethyl group (such as MTM: methylthiomethyl, PTM: phenylthiomethyl or Btm: benzylthiomethyl) , a carboxyl group, a C ⁇ acyl group (such as formyl, acetyl, fluoroacetyl, difluoroacetyl , trifluoroacetyl, chloroacetyl, dichloroacetyl , trichloroacetyl, propionyl, Pv: pivaloyl or tigloyl) , an arylcarbonyl group (such as benzoyl, benzoylformyl, benzoylpropion
  • an aryloxycarbonyl group such as Z: benzyloxycarbonyl , p-nitrobenzyloxycarbonyl or MOZ : p- methoxybenzyloxycarbonyl
  • a C 1 4 alkylaminocarbonyl group methylcarbamoyl, Ec : ethylcarbamoyl or n- propylcarbamoyl
  • an arylaminocarbonyl group such as phenylcarbamoyl
  • a trialkylsilyl group such as TMS : trimethylsilyl, TES : triethylsilyl , TIPS: triisopropylsilyl
  • DEIPS diethylisopropylsilyl
  • DMIPS dimethylisopropylsilyl
  • DTBMS di-t-butylmethylsilyl
  • IPDMS isopropyldimethylsilyl
  • TBD isopropyldimethylsily
  • t-butyldimethylsilyl a trialkylarylsilyl group (such as DPMS : diphenylmethylsilyl, TBDPS : t-butyldiphenylsilyl, TBMPS : t-butyldimethoxyphenylsilyl or TPS : triphenylsilyl) , an alkylsulfonyl group (such as Ms: methanesulfonyl or ethanesulfonyl) , or an arylsulfonyl group (such as benzenesulfonyl, Ts : p-toluenesulfonyl, p- chlorobenzenesulfonyl, MBS: p-methoxybenzenesulfonyl , m- nitrobenzenesulfonyl , iMds : 2 , 6-dimethoxy-4- methylbenzene
  • D may be a covalent bond, -CH,-, -0-, -S-, -S(O)-, -S(0) 2 -, -NR -, -C(0)-NR X -, -NR -C(O)- or -NR -C ⁇ 0)-
  • NR - (each of R and R which are independent of each other, is a hydrogen atom or a C ⁇ ., alkyl group) ,
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
  • Each of X , X , X , X and X which are independent of one another, may be a nitrogen atom or CR .
  • X , X , X and X which are independent of one another, may be a nitrogen atom or CR .
  • 2 another may be a nitrogen atom or CH, and each of X and
  • X which are independent of each other may be CR . More
  • X may be CR (R is a hydrogen atom or a halogen atom) .
  • R is a hydrogen atom or a halogen atom
  • at least one of X to X is a nitrogen atom.
  • R may be a hydrogen atom, a halogen atom or -E-G.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
  • Each of R , R , R and R wnich are independent of one another, may be a hydrogen atom, a halogen atom, a hydroxyl group, a C ⁇ alkyl group or a C 1 7 alkoxy group.
  • each of R , R , R , and R which are independent of one another may be a hydrogen atom, a C 1 7 alkyl group or a C ⁇ _ 7 alkoxy group.
  • the halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like.
  • the C ⁇ _ 7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like.
  • each of R 1 and R l3' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group or a C 6 ⁇ 14 aromatic group.
  • each of R 1 and R l3' which are independent of each other, is a hydrogen atom, a C,_ 7 alkyl group or a C 6 ⁇ 14 aromatic group
  • the C 1 _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl or n-heptyl .
  • the C 6 _ 14 aromatic group may be phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 1-indenyl, 2-indenyl, 3-indenyl, 4-indenyl, 5-indenyl, 6-indenyl, 7-indenyl, 1-indanyl, 2-indanyl, 4- indanyl, 5-indanyl, 1-fluorenyl, 2-fluorenyl, 3- fluorenyl, 4-fluorenyl, 9-fluorenyl or the like.
  • k is from 1 to 10
  • each of R and R " which are independent of each other, is a hydrogen atom or a C 1 7 alkyl group, may be mentioned, and preferably
  • G may be a hydrogen atom, a C 3 _ 10 cycloalkyl group, a C 3 _ 7 cycloalkenyl group, a C s _ 14 aromatic group, a C_ 12 heteroaromatic group or a C 4 _ 12 heteroalicyclic group, preferably a hydrogen atom, a C 5 _ 14 aromatic group, a C 4 _ 12 heteroaromatic group or a C 4 _ 12 heteroalicyclic group .
  • the C 3 _ 1Q cycloalkyl group may be cyclopropyl, 1- methylcyclopropyl, 2-methylcyclopropyl , 4- methylcyclohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[2.2. ljheptyl , bicyclo[3. i .
  • ljheptyl bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl, and the C 6 _ 10 cycloalkyl group may be preferably cyclohexyl, bicyclo[2.2. ljheptyl , bicyclo[3.1.
  • ljheptyl bicyclo[2.2.2]octyl, 1-adamantyl or 2-adamantyl; either of them may have at most 5 substituents in total (said substituent is a hydrogen atom, a C,_ 7 alkyl group, a C,_ 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a D hydroxyl group, a C._ 7 alkoxy group, a C ⁇ .
  • alkylthio group a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C 1 _, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulfamoyl group, a phenoxy group, a benzyloxy group, a tri-C 1 _ 7 alkylsilyloxy group, phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl or benzyl (each of said phenyl, naphthyl, furyl, thienyl, imidazolyl, pyridyl and benzyl may be substituted with at most 5 of C 1 _ 7 alkyl groups
  • substituents in total are hydrogen atom, a C ⁇ alkyl group, a C 3 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C ⁇ _ 7 alkoxy group, a C ⁇ _ 7 alkylthio group, a halogen atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C ⁇ _ 3 alkoxycarbonyl group,
  • the C ⁇ _ 7 alkyl group may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl or the like, preferably it may be methyl, ethyl, n-propyl or the like, and either of them may be substituted with a hydroxyl group;
  • the C 3 _ 7 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.
  • ljheptyl bicyclo[3.1. ljheptyl or the like, preferably it may be cyclopropyl, cyclohexyl or the like, and either of them may be substituted with a hydroxyl group;
  • the C 3 _ 7 cycloalkenyl group may be 1-cyclohexenyl, 2- cyclohexenyl, 3-cyclohexenyl , cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl, 2 , 5-bicyclo[2.2.
  • the C ⁇ _ 7 alkoxy group may be methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentyloxy, hexyloxy, heptyloxy or the like
  • the C 1 _ 7 alkylthio group may be methylthio, ethylthio, n-propylthio, i-propylthio, n-butylthio, i- butylthio, s-butylthio, t-butylthio, pentylthio, hexylthio, heptylthio, or the like
  • the tri-C ⁇ _ 7 alkylsilyloxy group may be trimethylsilyloxy, triethylsilyloxy,
  • ' n' means normal, ' i' means iso, 's' means secondary, ' t' means tertiary, ' c' means cyclo, ' Me' means a methyl group, ⁇ t' means an ethyl group, 'Pr' means a propyl group, ' Bu' means a butyl group, 'Pen' means a pentyl group, ' Hex' means a hexyl group, 'Ph' means a phenyl group, and ' Hal'means a halogen atom.
  • the C 3 _ 7 cycloalkenyl group is cyclohexenyl, cyclopentadienyl, 2- bicyclo[2.2. ijheptenyl or 2 , 5-bicyclo[2.2.
  • the C 6 _ 14 aromatic group is phenyl, naphthyl, indenyl, indanyl or fluorenyl
  • the C 1 _ 12 heteroaromatic group is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furazanyl, pyrazolyl, oxopyrazolyl , imidazolyl, oxoimidazolyl, triazolyl, oxotriazolyl, tetrazolyl, pyranyl, pyridyl, pyridonyl, pyridazinyl, pyridazinonyl, pyrimidinyl, pyrimidinonyi , pyrazinyl, triazinyl, tetrazinyl, indolyl, quinolyl, quinolonyl,
  • each of R and R which are independent of each- other is a hydrogen atom, a C ⁇ _ 7 alkyl group, a C._ 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (each of said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C 1 _ 7 alkoxy group, a C,_ 7 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C, alkoxycarbonyl group, a nitrile group, a carbamoyl group, a
  • each of R and R which are independent of each other is a hydrogen atom, a C 1 7 alkyl group, a C 3 7 cycloalkyl group, a C 3 _ 7 cycloalkenyl group (said alkyl group, cycloalkyl group and cycloalkenyl group may be substituted with a hydroxyl group) , a hydroxyl group, a C,_ 7 alkoxy group, a C 1 _ 1 alkylthio group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a nitro group, an amino group, a methylamino group, a dimethylamino group, an acetamide group, a methanesulfonylamide group, a carboxyl group, a C ⁇ _ 3 alkoxycarbonyl group, a nitrile group, a carbamoyl group, a sulf
  • R is a hydrogen atom or a C 17 alkyl group
  • 10 10' is a guanidyl group, an amidmo group, NR R (wherein
  • each of R and R which are independent of each other, is a hydrogen atom or a C 1 7 al -, ,kyl, group) or N + RIIR11'R11' ⁇
  • R is a hydrogen atom or a C 1 _ 1 alkyl group
  • D is -0- , -NR - (wherein R " is a hydrogen atom or a C,_ 7 alkyl group)
  • each of R , R , R and R which are independent of one another, is a hydrogen atom, a C 1-7 alkyl group or a C,_ 7
  • each of R and R which are independent of each other, is a hydrogen atom or a C 1 _ 1 alkyl group
  • R is C(0)OR (wherein R is a hydrogen atom or a
  • R is NR R (wherein each of R and
  • D is -O- or -NH-
  • X is CR (wherein R is a hydrogen atom or a halogen atom) .
  • the compound represented by the formula [ij of the present invention can be used for the purpose of the present invention either in the free form or in the form of a pharmaceutically acceptable salt.
  • the compound represented by the formula [ij, i.e. 6- membered heterocyclic-compound, can be prepared by the following synthetic methods.
  • a reaction solvent used in the preparation is stable under the reaction conditions, and is preferably so inert as not to inhibit the reaction.
  • the reaction solvent water, alcohols (such as methanol, ethanol, propanol, butanol and octanol) , cellosolves (such as methoxyethanol and ethoxyethanol) , aprotic polar organic solvents (such as dimethylformamide (DMF) , dimethylsulfoxide (DMSO) , dimethylacetamide, tetramethylurea, sulfolane, N,N- dimethylimidazolidinone (DMI), 1 , 3-dimethyl-3 , 4 , 5 , 6- tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA) ) , ethers (such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane)
  • solvents are optionally selected depending upon the reactivity of the aimed reaction, and are respectively used alone or in a mixture. In some cases, they are used as a non-aqueous solvent by using a suitable dehydrating agent or a drying agent.
  • suitable dehydrating agent or a drying agent used as a suitable dehydrating agent.
  • the above- mentioned solvents are merely examples which can be used in the reaction of the present invention, and the present invention is not limited to these conditions.
  • R 16 and R is a suitable leaving group for the nucleophilic substitution in the reaction, including halogen such as chlorine, bromine or iodine, and an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy or methanesuIfonyloxy] .
  • halogen such as chlorine, bromine or iodine
  • an aromatic or aliphatic sulfonyloxy group such as p-toluenesulfonyloxy, benzenesulfonyloxy or methanesuIfonyloxy] .
  • NR (wherein R is as defined above)
  • NR can be obtained by reacting a compound of the formula [ii] with a compound of the formula [ill] without a catalyst or in the presence of a catalyst.
  • the reaction is conducted usually in an appropriate solvent in the presence of a base.
  • aprotic polar organic solvents such as dimethylformamide, dimethylacetamide, tetramethylurea, N,N-dimethylimidazolidinone (DMI) , 1,3- dimethyl-3,4, 5, 6-tetrahydro-2 (IH) -pyrimidinone (DMPU) and hexamethylphosphoric triamide (HMPA)
  • ethers aromatic hydrocarbons, halogenated hydrocarbons, ketones, lower aliphatic acid esters, alkoxy alkanes and acetonitrile may, for example, be mentioned.
  • organic amines such as diisopropylethylamine, trimethylamine, triethylamine, N- methylmorpholine and pyridine
  • metal alkoxides such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide
  • inorganic alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate
  • alkali metal amides such as sodium amide
  • a group of palladium such as tetrakis ( triphenylpnosphme)palladium(0) , palladium (II) chloride and 1,3- bis (diphenylphosphino) propane/Pd 2 (dba) ,
  • a group of nickel such as dichloro[l , 3- bis (diphenylphosphino) propanejnickel (II) and tetrakis (triphenylphosphite) nickel (0)
  • a group of ruthenium such as dichlorotris (triphenylphosphine) ruthenium
  • a group of rhodium such as chlorotris (triphenylphosphine) rhodium
  • the reaction is conducted usually at a temperature ranging from -100°C to the boiling point of the solvent to be used in the reaction, preferably from 20°C to 150°C, for from 0.5 to 30 hours.
  • a temperature ranging from -100°C to the boiling point of the solvent to be used in the reaction preferably from 20°C to 150°C, for from 0.5 to 30 hours.
  • Examples for the reaction of a halopyridine with an alkylamine are described in J. Org. Chem, 1953, 18, 1484, Tetrahedron Lett, 1971, 1875, Chem. Ber, 1969, 102, 1161 and Reel. Trav. Chim. Pays-Bas, 1969, 88, 1391.
  • the reaction using a palladium catalyst is described in J. Org. Chem, 1996, 61, 7240 and ibid 1997, 62, 1568.
  • NR (wherein R is as defined above)
  • R is as defined above
  • NR can be obtained by nucleophilic substitution of a compound of the formula [vj with a compound of the formula [ivj .
  • R is chlorine, bromine or OC(0)OR (wherein R is a C ⁇ _ alkyl group or a phenyl group)].
  • a compound of the formula [l-2J can be obtained by nucleophilic substitution of a compound of the formula [vi] with a compound of the formula [lII-2J.
  • the reaction is usually conducted in a suitable organic solvent, and the reaction can be accelerated by using a suitable base as the case requires.
  • a suitable organic solvent aprotic polar organic solvents, ethers, aromatic hydrocarbons, halogenated hydrocarbons, alkoxy alkanes and acetonitrile may, for example, be mentioned.
  • organic amines such as diisopropylethylamine, trimethylamine, triethylamine, N- methylpiperidine, N-methylmorpholine, pyridine, 2,6- lutidine and collidine
  • metal alkoxides such as sodium methoxide, sodium ethoxide, lithium isopropoxide and potassium t-butoxide
  • inorganic alkali metal salts such as sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, sodium acetate and potassium acetate
  • alkali metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and 2,2,6,6- tetramethylpiperidide
  • alkali metals such as methyllithium, n-butyllithium
  • the reaction is conducted usually at a temperature ranging from -78°C to the boiling point of the solvent to be used in the reaction, for from 0.5 to 30 hours.
  • a compound of the formula [l-3J can be obtained by nucleophilic substitution of a compound of the formula [vilj with a compound of the formula [lV-2].
  • M is -NCO or -N(R )-C(0)-OR (wherein R is as defined above, R is a ⁇ _ 7 alkyl group or a phenyl group)].
  • R is as defined above, R is a ⁇ _ 7 alkyl group or a phenyl group.
  • NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [vill] with a compound of the formula [lll-2j.
  • the reaction can be conducted under the same conditions as in Process 3.
  • NR - (wherein R is as defined above), i.e. a compound of the formula [l-4], can be obtained by reacting a compound of the formula [lV-2] with a compound of the formula [ix] .
  • an intermediate of the formula [xill] can be obtained by solvolysis (by e.g. an alcohol or water) of a ⁇ -lactam of the formula [Xllj.
  • the ⁇ -lactarn can be obtained by cyclization of a compound of the formula [xi] that can be obtained by reacting a common olefination reagent (such as Wittig reagent) with a piperidone of the formula [xj, with a suitable isocyanate (such as ClS0 2 NCO) .
  • a common olefination reagent such as Wittig reagent
  • a piperidone of the formula [xj with a suitable isocyanate (such as ClS0 2 NCO) .
  • R and R are as defined above, and R is a hydrogen atom, C ⁇ _ 7 aliphatic acyl, C 5 _ 10 aromatic acyl or a protecting group].
  • an intermediate of the formula [xv] can be synthesized by conducting Arndt-Eistert reaction of a compound of the formula [XIVJ.
  • 4-amino-4-piperidyl acetate derivative can be obtained by reacting diazomethane with an acyl chloride or a mixed anhydride of the compound of the formula [XIVJ to obtain a diazoketone, followed by using a suitable catalyst (for example, a silver compound such as silver benzoate) or irradiating with light in the presence of a suitable alcohol.
  • a suitable catalyst for example, a silver compound such as silver benzoate
  • the protecting group is removed as the case requires, to obtain an intermediate of the formula [XIII].
  • the compound of the formula [XIVJ can be synthesized in accordance with a method as described in USP 3,313,819, USP 3,330,836 or J. Org. Chem., 1957, 22, 1061.
  • the protecting group is removed as the case requires, to obtain an intermediate of the formula [XVIJ .
  • NR (wherein R is as defined above) and Q is Li, Cu, MgBr, ZnBr, a trialkylstannyl group such as tributylstannyl or a trialkylsilyl group such as trimethylsilyl] .
  • the intermediate of the formula [XIIl] can be synthesized by various reactions from the compound of the formula [x] .
  • a compound of the formula LXIII-d] and a compound of the formula [xill-e] can be obtained, by reacting a compound of the formula [XXIIJ with a suitable oxidizing agent followed by suitable reaction treatment, and by reacting it with a suitable reducing agent, respectively.
  • the compound of the formula [xill-bj can be obtained by reacting the piperidone with a carboxylate derivative of the formula [XXIVJ .
  • the compound of the formula [xill-b] can be converted to a thiol of the formula [xill-2b] or 'an amine of the formula [xill-lbj, as the above-mentioned compound of the formula [xillj.
  • the compound of the formula [xxil] can be synthesized in accordance with a method as described in J. Org. Chem., 1998, 63, 4554. The protecting group is removed to obtain the intermediate of the formula [XIIl], [xill-bj, [xill-dj or [xill-ej if 1 required.
  • the intermediate of the formula [XIIl] can be synthesized also by Michael addition of various olefin derivatives.
  • malonate, malonitrile or a cyano acetate derivative is treated with a piperidone of the formula [x] to synthesize a compound of the formula [xxv], [XXVIJ or [XXVIIJ, respectively.
  • ammonia is added therewith, an azide is added therewith followed by reacting a suitable reducing agent therewith, or an amine having a suitable protecting group such as benzylamine is added therewith followed by removing the protecting group, to obtain a compound of the formula [XXVIII], [XXIX] or [XXXJ, respectively.
  • the compound of the formula [XXVIII] can be lead to an intermediate of the formula [xvj by known methods (such as hydrolysis of one ester followed by decarboxylation) , and the protecting group is removed to obtain the intermediate of the formula [XIIl] as the case requires.
  • the cyano group is hydrolyzed, and the intermediate of the formula [XIIl] can be obtained in the same manner as for the compound of the formula [XXVIIIJ.
  • a cyano acetate derivative of the formula [XXXIJ obtained by decarboxylation is hydrolyzed to obtain an intermediate of the formula [xv], and the protecting group is removed to obtain the intermediate of the formula [xillj.
  • an amide derivative of the formula [XXXIIJ and an alkyl amino of the formula [XXXIIIJ can be synthesized by known methods.
  • an amino group is introduced to an ⁇ -unsaturated carboxylic acid of the formula [XXXIV] or an ⁇ -unsaturated nitrile of the formula [XXXVJ, which can be synthesized by known methods, by Michael addition in the same manner as in the Reaction
  • an intermediate of the formula [xvi] or [XIIl] can be also obtained by means of Overman rearrangement (refer to e.g. J. Am. Chem. Soc. 1974, 96, 597) .
  • the compound of the formula [XXXVIIJ can be prepared by the treatment of the alcohol of the formula [XXVI] that is synthesized by known methods (such as Wittig reaction) with an acetonitrile derivative (such as Cl.CCN) .
  • the precursor can be converted to the compound of the formula [XXXVIII] under suitable conditions (for example, reflux under heating in a solvent having a high boiling point such as xylene, or a reaction under coexistence of a metal agent such as trifluoromercury acetate) .
  • suitable conditions for example, reflux under heating in a solvent having a high boiling point such as xylene, or a reaction under coexistence of a metal agent such as trifluoromercury acetate.
  • the vinyl group of the compound of the formula [XXXVIII] is converted to a carboxylate derivative by a suitable oxidation method (such as ozone oxidation) , and the protecting group is removed if necessary, to obtain the intermediate of the formula [XVI] .
  • the compound of the formula [XXXVIII] can be lead to the intermediate of the formula [XHI-d] in such a manner that it is lead to an alcohol by a known suitable reducing agent, and the protecting group is removed as the case requires .
  • the intermediate may be further oxidized by a known suitable oxidation method, the protecting group is removed as the case requires, and the intermediate of the formula [XIII] can be obtained.
  • G is a C._, 2 heteroaromatic group, a C,_.. heteroalicyclic group, a C 3 _ ⁇ z cycloalkyl group, a C,_ 7 cycloalkenyl group or a C,_ 14 aromatic group, and each of L and L which are independent of each other, is -0-, -S- or -NR - (wherein R " is as defined above)].
  • a compound of the formula [XXXXI] can be synthesized by nucleophilic substitution of a compound of the formula [XXXX] with an alcohol of the formula [XXXIX] wherein L is 0, a thiol of the formula [XXXIX] wherein L is S or an amine of the i . 15 15 formula [XXXIX] wherein L is NR (wherein R is as l ⁇ defined above) .
  • R is a suitable leaving group. The protecting group of the obtained compound of the formula [XXXI] is removed, as the case requires, and can be used as a substituent of R .
  • a phenol of the formula [XXXIX(G is a phenyl group)] wherein L is 0, and a thiophenol of the formula [XXXIX(G is a phenyl group)] wherein L is S, can be lead to alcohols of the formula [XXXXIIIJ by using a compound of the formula [XXXXIIJ. under suitable basic conditions, in accordance with methods as described in Bull. Chem. Soc.

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
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Abstract

L'invention concerne un composé hétérocyclique à 6 éléments ou son sel représenté par la formule (I), dans laquelle A est représenté par la formule (a), (b) ou (c).
PCT/JP1999/003214 1998-06-19 1999-06-16 Composes heterocycliques utilises comme agents hypoglecymiques WO1999065881A1 (fr)

Priority Applications (1)

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AU41670/99A AU4167099A (en) 1998-06-19 1999-06-16 Heterocyclic compounds as hypoglycemic agents

Applications Claiming Priority (4)

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JP10/172435 1998-06-19
JP17243598 1998-06-19
JP11/140693 1999-05-20
JP14069399 1999-05-20

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2005003103A3 (fr) * 2003-06-30 2005-11-03 Astrazeneca Ab Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
US7015329B2 (en) 2003-10-31 2006-03-21 Janssen Pharmaceutica N. V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
WO2007063012A1 (fr) * 2005-12-01 2007-06-07 F. Hoffmann-La Roche Ag Derives de piperidine substitues par un heteroaryle en tant qu'inhibiteurs de l-cpt1
US7378436B2 (en) 2003-06-17 2008-05-27 Pfizer Inc. Compounds
US8410150B2 (en) 2007-03-09 2013-04-02 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
US8431575B2 (en) 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8680282B2 (en) 2007-08-01 2014-03-25 University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
CN115650903A (zh) * 2022-10-31 2023-01-31 苏州天马医药集团天吉生物制药有限公司 一种起始氨基酸Boc-Pip（Fmoc）-OH的制备方法

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EP0127098A2 (fr) * 1983-05-25 1984-12-05 Takeda Chemical Industries, Ltd. Dérivés du bêta-amino-gama-triméthylammonio-butyrate, leur préparation et leur utilisation

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EP0127098A2 (fr) * 1983-05-25 1984-12-05 Takeda Chemical Industries, Ltd. Dérivés du bêta-amino-gama-triméthylammonio-butyrate, leur préparation et leur utilisation

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DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; POPOVA, L. M. ET AL: "Reaction of 2,4,6-trifluoropyrimidines with amino acids", XP002117432, retrieved from STN Database accession no. 130:209942 *
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7378436B2 (en) 2003-06-17 2008-05-27 Pfizer Inc. Compounds
WO2005003103A3 (fr) * 2003-06-30 2005-11-03 Astrazeneca Ab Nouveaux heterocycles 2,4,6-trisubstitues et utilisations de ceux-ci
US7498351B2 (en) 2003-10-31 2009-03-03 Janssen Pharmaceutica N.V. 4-((Phenoxyalkyl)thio)-phenoxyacetic acids and analogs
US7015329B2 (en) 2003-10-31 2006-03-21 Janssen Pharmaceutica N. V. 4-((phenoxyalkyl)thio)-phenoxyacetic acids and analogs
AU2006319247B2 (en) * 2005-12-01 2010-03-11 F. Hoffmann-La Roche Ag Heteroaryl substituted piperidine derivatives as L-CPT1 inhibitors
US7645776B2 (en) 2005-12-01 2010-01-12 Hoffmann-La Roche Inc. Heteroaryl substituted piperidine derivatives which are L-CPT1 inhibitors
WO2007063012A1 (fr) * 2005-12-01 2007-06-07 F. Hoffmann-La Roche Ag Derives de piperidine substitues par un heteroaryle en tant qu'inhibiteurs de l-cpt1
RU2396269C2 (ru) * 2005-12-01 2010-08-10 Ф.Хоффманн-Ля Рош Аг Производные гетероарилзамещенного пиперидина в качестве ингибиторов печеночной карнитин пальмитоилтрансферазы (l-cpt1)
US8410150B2 (en) 2007-03-09 2013-04-02 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
US8680282B2 (en) 2007-08-01 2014-03-25 University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
US8431575B2 (en) 2010-02-18 2013-04-30 Transtech Pharma, Inc. Phenyl-heteroaryl derivatives and methods of use thereof
US8741900B2 (en) 2010-02-18 2014-06-03 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
US9045461B2 (en) 2010-02-18 2015-06-02 Transtech Pharma, Llc Phenyl-heteroaryl derivatives and methods of use thereof
CN115650903A (zh) * 2022-10-31 2023-01-31 苏州天马医药集团天吉生物制药有限公司 一种起始氨基酸Boc-Pip（Fmoc）-OH的制备方法
CN115650903B (zh) * 2022-10-31 2024-05-28 苏州天马医药集团天吉生物制药有限公司 一种起始氨基酸Boc-Pip（Fmoc）-OH的制备方法

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